This invention relates to novel optical probes for use in physiological function monitoring, particularly indole and benzoindole compounds.
Dynamic monitoring of physiological functions of patients at the bedside is highly desirable in order to minimize the risk of acute renal failure brought about by various clinical, physiological, and pathological conditions (C. A. Rabito, L. S. T. Fang, and A. C. Waltman, Renal function in patients at risk with contrast material-induced acute renal failure: Noninvasive real-time monitoring, Radiology 1993, 186, 851-854; N. L. Tilney, and J. M. Lazarus, Acute renal failure in surgical patients: Causes, clinical patterns, and care, Surgical Clinics of North America, 1983, 63, 357-377; B. E. VanZe, W. E. Hoy, and J. R. Jaenike, Renal injury associated with intravenous pyelography in non-diabetic and diabetic patients, Annals of Internal Medicine, 1978, 89, 51-54; S. Lundqvist, G. Edbom, S. Groth, U. Stendahl, and S.-O. Hietala, lohexol clearance for renal function measurement in gynecologic cancer patients, Acta Radiologica, 1996, 37, 582-586; P. Guesry, L. Kaufman, S. Orlof, J. A. Nelson, S. Swann, and M. Holliday, Measurement of glomerular filtration rate by fluorescent excitation of non-radioactive meglumine iothalamate, Clinical Nephrology, 1975, 3, 134-138). This monitoring is particularly important in the case of critically ill or injured patients because a large percentage of these patients face the risk of multiple organ failure (MOF), resulting in death (C. C. Baker et al., Epidemiology of Trauma Deaths, American Journal of Surgery, 1980, 144-150; R. G. Lobenhofer et al., Treatment Results of Patients with Multiple Trauma: An Analysis of 3406 Cases Treated Between 1972 and 1991 at a German Level I Trauma Center, Journal of Trauma, 1995, 38, 70-77). MOF is a sequential failure of lung, liver, and kidneys, and is incited by one or more severe causes such as acute lung injury (ALI), adult respiratory distress syndrome (ARDS), hypermetabolism, hypotension, persistent inflammatory focus, or sepsis syndrome. The common histological features of hypotension and shock leading to MOF include tissue necrosis, vascular congestion, interstitial and cellular edema, hemorrhage, and microthrombi. These changes affect the lung, liver, kidneys, intestine, adrenal glands, brain, and pancreas, in descending order of frequency (J. Coalson, Pathology of Sepsis, Septic Shock, and Multiple Organ Failure. In New Horizons: Multiple Organ Failure, D. J. Bihari and F. B. Cerra (Eds). Society of Critical Care Medicine, Fullerton, Calif., 1986, pp. 27-59). The transition from early stages of trauma to clinical MOF is marked by the extent of liver and renal failure and a change in mortality risk from about 30% to about 50% (F. B. Cerra, Multiple Organ Failure Syndrome. In New Horizons: Multiple Organ Failure, D. J. Bihari and F. B. Cerra (Eds). Society of Critical Care Medicine, Fullerton, Calif., 1989, pp. 1-24).
Serum creatinine measured at frequent intervals by clinical laboratories is currently the most common way of assessing renal function and following the dynamic changes in renal function which occur in critically ill patients (P. D. Dollan, E. L. Alpen, and G. B. Theil, A clinical appraisal of the plasma concentration and endogenous clearance of creatinine, American Journal of Medicine, 1962, 32, 65-79; J. B. Henry (Ed). Clinical Diagnosis and Management by Laboratory Methods, 17th Edition, W. B. Saunders, Philadelphia, Pa., 1984); C. E. Speicher, The right test: A physician""s guide to laboratory medicine, W. B. Saunders, Philadelphia, Pa., 1989). These values are frequently misleading, since age, state of hydration, renal perfusion, muscle mass, dietary intake, and many other clinical and anthropometric variables affect the value. In addition, a single value returned several hours after sampling is difficult to correlate with other important physiologic events such as blood pressure, cardiac output, state of hydration and other specific clinical events (e.g., hemorrhage, bacteremia, ventilator settings and others). An approximation of glomerular filtration rate can be made via a 24-hour urine collection, but this requires 24 hours to collect the sample, several more hours to analyze the sample, and a meticulous bedside collection technique. New or repeat data are equally cumbersome to obtain. Occasionally, changes in serum creatinine must be further adjusted based on the values for urinary electrolytes, osmolality, and derived calculations such as the xe2x80x9crenal failure indexxe2x80x9d or the xe2x80x9cfractional excretion of sodium.xe2x80x9d These require additional samples of serum collected contemporaneously with urine samples and, after a delay, precise calculations. Frequently, dosing of medication is adjusted for renal function and thus can be equally as inaccurate, equally delayed, and as difficult to reassess as the values upon which they are based. Finally, clinical decisions in the critically ill population are often as important in their timing as they are in their accuracy.
Exogenous markers such as inulin, iohexol, 51Cr-EDTA, Gd-DTPA, or 99mTc-DTPA have been reported to measure the glomerular filtration rate (GFR) (P. L. Choyke, H. A. Austin, and J. A. Frank, Hydrated clearance of gadolinium-DTPA as a measurement of glomerular filtration rate, Kidney International, 1992, 41, 1595-1598; M. F. Twedle, X. Zhang, M. Fernandez, P. Wedeking, A. D. Nunn, and H. W. Strauss, A noninvasive method for monitoring renal status at bedside, Invest. Radiol., 1997, 32, 802-805; N. Lewis, R. Kerr, and C. Van Buren, Comparative evaluation of urographic contrast media, inulin, and 99mTc-DTPA clearance methods for determination of glomerular filtration rate in clinical transplantation, Transplantation, 1989, 48, 790-796). Other markers such as 123I and 125I labeled o-iodohippurate or 99mTc-MAG3 are used to assess tubular secretion process (W. N. Tauxe, Tubular Function, in Nuclear Medicine in Clinical Urology and Nephrology, W. N. Tauxe and E. V. Dubovsky, Editors, pp. 77-105, Appleton Century Crofts, East Norwalk, 1985; R. Muller-Suur, and C. Muller-Suur, Glomerular filtration and tubular secretion of MAG3 in rat kidney, Journal of Nuclear Medicine, 1989, 30, 1986-1991). However, these markers have several undesirable properties such as the use of radioactivity or ex-vivo handling of blood and urine samples. Thus, in order to assess the status and to follow the progress of renal disease, there is a considerable interest in developing a simple, safe, accurate, and continuous method for determining renal function, preferably by non-radioactive procedures. Other organs and physiological functions that would benefit from real-time monitoring include the heart, the liver, and blood perfusion, especially in organ transplant patients.
Hydrophilic, anionic substances are generally recognized to be excreted by the kidneys (F. Roch-Ramel, K. Besseghir, and H. Murer, Renal excretion and tubular transport of organic anions and cations, Handbook of Physiology, Section 8, Neurological Physiology, Vol. II, E. E. Windhager, Editor, pp. 2189-2262, Oxford University Press, New York, 1992; D. L. Nosco, and J. A. Beaty-Nosco, Chemistry of technetium radiopharmaceuticals 1: Chemistry behind the development of technetium-99m compounds to determine kidney function, Coordination Chemistry Reviews, 1999, 184, 91-123). It is further recognized that drugs bearing sulfonate residues exhibit improved clearance through the kidneys (J. Baldas, J. Bonnyman, Preparation, HPLC studies and biological behavior of techentium-99m and 99mTcNO-radiopharmaceuticals based on quinoline type ligands, Nucl. Med. Biol., 1999, 19, 491-496; L. Hansen, A. Taylor, L., L. G. Marzilli, Synthesis of the sulfonate and phosphonate derivatives of mercaptoacetyltriglycine. X-ray crystal structure of Na2[ReO(mercaptoacetylglycylglycylaminomethane-sulfonate)]3H2O, Met.-Based Drugs, 1994, 1, 31-39).
Assessment of renal function by continuously monitoring the blood clearance of exogenous optical markers, viz., fluorescein bioconjugates derived from anionic polypeptides, has been developed by us and by others (R. B. Dorshow, J. E. Bugaj, B. D. Burleigh, J. R. Duncan, M. A. Johnson, and W. B. Jones, Noninvasive fluorescence detection of hepatic and renal function, Journal of Biomedical Optics, 1998, 3, 340-345; M. Sohtell et al., FITC-lnulin as a Kidney Tubule Marker in the Rat, Acta. Physiol. Scand., 1983, 119, 313-316, each of which is expressly incorporated herein by reference). The main drawback of high molecular weight polypeptides is that they are immunogenic. In addition, large polymers with narrow molecular weight distribution are difficult to prepare, especially in large quantities. Thus, there is a need in the art to develop low molecular weight compounds that absorb and/or emit light that can be used for assessing renal, hepatic, cardiac and other organ functions.
The present invention overcomes these difficulties by incorporating hydrophilic anionic or polyhydroxy residues in the form of sulfates, sulfonates, sulfamates and strategically positioned hydroxyl groups. Thus, the present invention is related to novel dyes containing multiple hydrophilic moieties and their use as diagnostic agents for assessing organ function.
The novel compositions of the present invention comprise dyes of Formulas 1 to 6 which are hydrophilic and absorb light in the visible and near infrared regions of the electromagnetic spectrum. The ease of modifying the clearance pathways of the dyes after in vivo administration permits their use for physiological monitoring. Thus, blood protein-binding compounds are useful for angiography and organ perfusion analysis, which is particularly useful in organ transplant and critical ill patients. Predominant kidney clearance of the dyes enables their use for dynamic renal function monitoring, and rapid liver uptake of the dyes from blood serves as a useful index for the evaluation of hepatic function.
As illustrated in FIGS. 1-7, these dyes are designed to inhibit aggregation in solution by preventing intramolecular and intermolecular induced hydrophobic interactions.
The present invention relates particularly to the novel compounds comprising indoles of the general Formula 1
wherein R3, R4, R5, R6, and R7, and Y1 are independently selected from the group consisting of xe2x80x94H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, xe2x80x94SO3T, xe2x80x94CO2T, xe2x80x94OH, xe2x80x94(CH2aSO3T, xe2x80x94(CH2)aOSO3(CH2)aNHSO3T, xe2x80x94(CH2)aCO2(CH2)bSO3T, xe2x80x94(CH2)aOCO(CH2)bSO3T, xe2x80x94(CH2)aCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCO(CH2)bSO3T, xe2x80x94(CH2)aNHCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCSNH(CH2)bSO3T, xe2x80x94(CH2)aOCONH(CH2)bSO3T, xe2x80x94(CH2)aPO3HT, xe2x80x94(CH2)aPO3T2, xe2x80x94(CH2)aOPO3HT, xe2x80x94(CH2)aOPO3T2, xe2x80x94(CH2)aNHPO3HT, xe2x80x94(CH2)aNHPO3T2, xe2x80x94(CH2) CO2(CH2)bPO3HT, xe2x80x94(CH2)aCO2(CH2)bPO3T2, xe2x80x94(CH2)aOCO(CH2)bPO3HT, xe2x80x94(CH2)aOCO(CH2)bPO3T2, xe2x80x94(CH2)aCONH(CH2)bPO3HT, xe2x80x94(CH2)aCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCO(CH2)bPO3HT, xe2x80x94(CH2)aNH(CH2)bPO3T2, xe2x80x94(CH2)aNHCONH(CH2)bPO3HT, xe2x80x94(CH2)aNHCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCSNH(CH2)bPO3HT, xe2x80x94(CH2)aNHCSNH(CH2)bPO3T2, xe2x80x94(CH2)aOCONH(CH2)bPO3HT, and xe2x80x94(CH2)aOCONH(CH2)bPO3T2, xe2x80x94CH2(CH2xe2x80x94Oxe2x80x94CH2)cxe2x80x94CH2xe2x80x94OH, xe2x80x94(CH2)dxe2x80x94CO2T, xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)exe2x80x94CH2xe2x80x94CO2T, xe2x80x94(CH2)fxe2x80x94NH2, xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)gxe2x80x94CH2xe2x80x94NH2, xe2x80x94(CH2)hxe2x80x94N(Ra)xe2x80x94(CH2)ixe2x80x94CO2T, and xe2x80x94(CH2)jxe2x80x94N(Rb)xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)kxe2x80x94CH2xe2x80x94CO2T; W1 is selected from the group consisting of xe2x80x94CRcRd, xe2x80x94Oxe2x80x94, xe2x80x94NRc, xe2x80x94Sxe2x80x94, and xe2x80x94Se; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; Ra, Rb, Rc, and Rd are defined in the same manner as Y1; T is either H or a negative charge.
The present invention also relates to the novel compounds comprising benzoindoles of general Formula 2
wherein R8, R9, R10, R11, R12, R13, R14, and Y2 are independently selected from the group consisting of xe2x80x94H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, xe2x80x94SO3T, xe2x80x94CO2T, xe2x80x94OH, xe2x80x94(CH2)aSO3T, xe2x80x94(CH2)aOSO3T, xe2x80x94(CH2)aNHSO3T, xe2x80x94(CH2)aCO2(CH2)bSO3T, xe2x80x94(CH2)aOCO(CH2)bSO3T, xe2x80x94(CH2)aCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCO(CH2)bSO3T, xe2x80x94(CH2)aNHCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCSNH(CH2)bSO3T, xe2x80x94(CH2)aOCONH(CH2)bSO3T, xe2x80x94(CH2)aPO3HT, xe2x80x94(CH2)aPO3T2, xe2x80x94(CH2)aOPO3HT, xe2x80x94(CH2)aOPO3T2, xe2x80x94(CH2)aNHPO3HT, xe2x80x94(CH2)aNHPO3T2, xe2x80x94(CH2)aCO2(CH2)bPO3HT, xe2x80x94(CH2)aCO2(CH2)bPO3T2, xe2x80x94(CH2)aOCO(CH2)bPO3HT, xe2x80x94(CH2)aOCO(CH2)bPO3T2, xe2x80x94(CH2)aCONH(CH2)bPO3HT, xe2x80x94(CH2)aCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCO(CH2)bPO3HT, xe2x80x94(CH2)aNHCO(CH2)bPO3T2, xe2x80x94(CH2)aNHCONH(CH2)bPO3HT, xe2x80x94(CH2)aNHCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCSNH(CH2)bPO3HT, xe2x80x94(CH2)aNHCSNH(CH2)bPO3T2, xe2x80x94(CH2)aOCONH(CH2)bPO3HT, and xe2x80x94(CH2)aOCONH(CH2)bPO3T2, xe2x80x94CH2(CH2xe2x80x94Oxe2x80x94CH2)cxe2x80x94CH2xe2x80x94OH, xe2x80x94(CH2)dxe2x80x94CO2T, xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)exe2x80x94CH2xe2x80x94CO2T, xe2x80x94(CH2)fxe2x80x94NH2, xe2x80x94CH2xe2x80x94(CH2Oxe2x80x94CH2)gxe2x80x94CH2xe2x80x94NH2, xe2x80x94(CH2)hxe2x80x94N(Ra)xe2x80x94(CH2)ixe2x80x94CO2T, and xe2x80x94(CH2)jxe2x80x94N(Rb)xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)kxe2x80x94CH2xe2x80x94CO2T; W2 is selected from the group consisting of xe2x80x94CRcRd, xe2x80x94Oxe2x80x94, xe2x80x94NRc, xe2x80x94Sxe2x80x94, and xe2x80x94Se; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; Ra, Rb, Rc, and Rd are defined in the same manner as Y2; T is either H or a negative charge.
The present invention also relates to the novel composition comprising cyanine dyes of general Formula 3
wherein R15, R16, R17, R18, R19, R20, R21, R22, R23, Y3, and Z3 are selected from the group consisting of xe2x80x94H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, xe2x80x94SO3T, xe2x80x94CO2T, xe2x80x94OH, xe2x80x94(CH2)aSO3T, xe2x80x94(CH2)aOSO3T, xe2x80x94(CH2)aNHSO3T, xe2x80x94(CH2)aCO2(CH2)bSO3T, xe2x80x94(CH2)aOCO(CH2)bSO3T, xe2x80x94(CH2)aCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCO(CH2)bSO3T, xe2x80x94(CH2)aNHCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCSNH(CH2)bSO3T, xe2x80x94(CH2)aOCONH(CH2)bSO3T, xe2x80x94(CH2)aPO3HT, xe2x80x94(CH2)aPO3T2, xe2x80x94(CH2)aOPO3HT, xe2x80x94(CH2)aOPO3T2, xe2x80x94(CH2)aNHPO3HT, xe2x80x94(CH2)aNHPO3T2, (CH2)aCO2(CH2)bPO3HT, xe2x80x94(CH2)aCO2(CH2)bPO3T2, xe2x80x94(CH2)aOCO(CH2)bPO3HT, xe2x80x94(CH2)aOCO(CH2)bPO3T2, xe2x80x94(CH2)aCONH(CH2)bPO3HT, xe2x80x94(CH2)aCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCO(CH2)bPO3HT, xe2x80x94(CH2)aNHCO(CH2)bPO3T2, xe2x80x94(CH2)aNHCONH(CH2)bPO3HT, xe2x80x94(CH2)aNHCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCSNH(CH2)bPO3HT, xe2x80x94(CH2)aNHCSNH(CH2)bPO3T2, xe2x80x94(CH2)aOCONH(CH2)bPO3HT, and xe2x80x94(CH2)aOCONH(CH2)bPO3T2, xe2x80x94CH2(CH2xe2x80x94Oxe2x80x94CH2)cxe2x80x94CH2xe2x80x94OH, xe2x80x94(CH2)dxe2x80x94CO2T, xe2x80x94CH2xe2x80x94(CH2Oxe2x80x94CH2)exe2x80x94CH2xe2x80x94CO2T, xe2x80x94(CH2)txe2x80x94NH2, xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)gxe2x80x94CH2xe2x80x94NH2, xe2x80x94(CH2)hxe2x80x94N(Ra)xe2x80x94(CH2)ixe2x80x94CO2T, and xe2x80x94(CH2)jxe2x80x94N(Rb)xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)kxe2x80x94CH2xe2x80x94CO2T; W3 and X3 are selected from the group consisting of xe2x80x94CRcRd, xe2x80x94Oxe2x80x94, xe2x80x94NRc, xe2x80x94Sxe2x80x94, and xe2x80x94Se; V3 is a single bond or is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sexe2x80x94, and xe2x80x94NRa; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; a3 and b3 vary from 0 to 5; Ra, Rb, Rc, and Rd are defined in the same manner as Y3; T is either H or a negative charge.
The present invention further relates to the novel composition comprising cyanine dyes of general Formula 4
wherein R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, Y4, and Z4 are independently selected from the group consisting of xe2x80x94H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, xe2x80x94SO3T, xe2x80x94CO2T, xe2x80x94OH, xe2x80x94(CH2)aSO3T, xe2x80x94(CH2)aOSO3T, xe2x80x94(CH2)aNHSO3T, xe2x80x94(CH2)aCO2(CH2)bSO3T, xe2x80x94(CH2)aOCO(CH2)bSO3T, xe2x80x94(CH2)aCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCO(CH2)bSO3T, xe2x80x94(CH2)aNHCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCSNH(CH2)bSO3T, xe2x80x94(CH2)aOCONH(CH2)bSO3T, xe2x80x94(CH2)aPO3HT, xe2x80x94(CH2)aPO3T2, xe2x80x94(CH2)aOPO3HT, xe2x80x94(CH2)aOPO3T2, xe2x80x94(CH2)aNHPO3HT, xe2x80x94(CH2)aNHPO3T2, xe2x80x94(CH2)aCO2(CH2)bPO3HT, xe2x80x94(CH2)aCO2(CH2)bPO3T2, xe2x80x94(CH2)aOCO(CH2)bPO3HT, xe2x80x94(CH2)aOCO(CH2)bPO3T2, xe2x80x94(CH2)aCONH(CH2)bPO3HT, xe2x80x94(CH2)aCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCO(CH2)bPO3HT, xe2x80x94(CH2)aNHCO(CH2)bPO3T2, xe2x80x94(CH2)aNHCONH(CH2)bPO3HT, xe2x80x94(CH2)aNHCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCSNH(CH2)bPO3HT, xe2x80x94(CH2)aNHCSNH(CH2)bPO3T2, xe2x80x94(CH2)aOCONH(CH2)bPO3HT, and xe2x80x94(CH2)aOCONH(CH2)bPO3T2, xe2x80x94CH2(CH2xe2x80x94Oxe2x80x94CH2)cxe2x80x94CH2xe2x80x94OH, xe2x80x94(CH2)dxe2x80x94CO2T, xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)exe2x80x94CH2xe2x80x94CO2T, xe2x80x94(CH2)fxe2x80x94NH2, xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)gxe2x80x94CH2xe2x80x94NH2, xe2x80x94(CH2)hxe2x80x94N(Ra)xe2x80x94(CH2)ixe2x80x94CO2T, and xe2x80x94(CH2)jxe2x80x94N(Rb)xe2x80x94CH2xe2x80x94(CH2xe2x80x94xe2x80x94Oxe2x80x94CH2)kxe2x80x94CH2xe2x80x94CO2T; W4 and X4 are selected from the group consisting of xe2x80x94CRcRd, xe2x80x94Oxe2x80x94, xe2x80x94NRc, xe2x80x94Sxe2x80x94, and xe2x80x94Se; V4 is a single bond or is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sexe2x80x94, and xe2x80x94NRa; a4 and b4 vary from 0 to 5; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; Ra, Rb, Rc, and Rd are defined in the same manner as Y4; T is either H or a negative charge.
The present invention also relates to the novel composition comprising cyanine dyes of general Formula 5
wherein R37, R38, R39, R40, R41, R42, R43, R44, R45, Y5, and Z5 are independently selected from the group consisting of xe2x80x94H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, xe2x80x94SO3T, xe2x80x94CO2T, xe2x80x94OH, xe2x80x94(CH2)aSO3T, xe2x80x94(CH2)aOSO3T, xe2x80x94(CH2)aNHSO3T, xe2x80x94(CH2)aCO2(CH2)bSO3T, xe2x80x94(CH2)aOCO(CH2)bSO3T, xe2x80x94(CH2)aCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCO(CH2)bSO3T, xe2x80x94(CH2)aNHCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCSNH(CH2)bSO3T, xe2x80x94(CH2)aOCONH(CH2)bSO3T, xe2x80x94(CH2)aPO3HT, xe2x80x94(CH2)aPO3T2, xe2x80x94(CH2)aOPO3HT, xe2x80x94(CH2)aOPO3T2, xe2x80x94(CH2)aNHPO3HT, xe2x80x94(CH2)aNHPO3T2, xe2x80x94(CH2)aCO2(CH2)bPO3HT, xe2x80x94(CH2)aCO2(CH2)bPO3T2, xe2x80x94(CH2)aOCO(CH2)bPO3HT, xe2x80x94(CH2)aOCO(CH2)bPO3T2, xe2x80x94(CH2)aCONH(CH2)bPO3HT, xe2x80x94(CH2)aCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCO(CH2)bPO3HT, xe2x80x94(CH2)aNHCO(CH2)bPO3T2, xe2x80x94(CH2)aNHCONH(CH2)bPO3HT, xe2x80x94(CH2)aNHCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCSNH(CH2)bPO3HT, xe2x80x94(CH2)aNHCSNH(CH2)bPO3T2, xe2x80x94(CH2)aOCONH(CH2)bPO3HT, and xe2x80x94(CH2)aOCONH(CH2)bPO3T2, xe2x80x94CH2(CH2xe2x80x94Oxe2x80x94CH2)cxe2x80x94CH2xe2x80x94OH, xe2x80x94(CH2)dxe2x80x94CO2T, xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)exe2x80x94CO2T, xe2x80x94(CH2)fxe2x80x94NH2, xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)gxe2x80x94CH2xe2x80x94NH2, xe2x80x94(CH2)hxe2x80x94N(Ra)xe2x80x94(CH2)ixe2x80x94CO2T, and xe2x80x94(CH2)jxe2x80x94N(Rb)xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)kxe2x80x94CH2xe2x80x94CO2T; W5 and X5 are selected from the group consisting of xe2x80x94CRcRd, xe2x80x94Oxe2x80x94, xe2x80x94NRc, xe2x80x94Sxe2x80x94, and xe2x80x94Se; V5 is a single bond or is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sexe2x80x94, and xe2x80x94NRa; D5 is a single or a double bond; A5, B5 and E5 may be the same or different and are selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sexe2x80x94, xe2x80x94Pxe2x80x94, xe2x80x94NRa, xe2x80x94CRcRd, CRc, alkyl, and xe2x80x94Cxe2x95x90O; A5, B5, D5, and E5 may together form a 6 or 7 membered carbocyclic ring or a 6 or 7 membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or a sulfur atom; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; a5 and b5 vary from 0 to 5; Ra, Rb, Rc, and Rd are defined in the same manner as Y5; T is either H or a negative charge.
The present invention also relates to the novel composition comprising cyanine dyes of general Formula 6
wherein R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57 and R58, Y6, and Z6 are independently selected from the group consisting of xe2x80x94H, C1-C10 alkoxyl, C1-C10 polyalkoxyalkyl, C1-C20 polyhydroxyalkyl, C5-C20 polyhydroxyaryl, saccharides, amino, C1-C10 aminoalkyl, cyano, nitro, halogen, hydrophilic peptides, arylpolysulfonates, C1-C10 alkyl, C1-C10 aryl, xe2x80x94SO3T, xe2x80x94CO2T, xe2x80x94OH, xe2x80x94(CH2)aSO3T, xe2x80x94(CH2)OSO3T, xe2x80x94(CH2)aNHSO3T, xe2x80x94(CH2)aCO2(CH2)bSO3T, xe2x80x94(CH2)aOCO(CH2)bSO3T, xe2x80x94(CH2)aCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCO(CH2)bSO3T, xe2x80x94(CH2)aNHCONH(CH2)bSO3T, xe2x80x94(CH2)aNHCSNH(CH2)bSO3T, xe2x80x94(CH2)aOCONH(CH2)bSO3T, xe2x80x94(CH2)aPO3HT, xe2x80x94(CH2)aPO3T2, (CH2)aOPO3HT, xe2x80x94(CH2)aOPO3T2, xe2x80x94(CH2)aNHPO3HT, xe2x80x94(CH2)aNHPO3T2, (CH2)aCO2(CH2)bPO3HT, xe2x80x94(CH2)aCO2(CH2)bPO3T2, xe2x80x94(CH2)aOCO(CH2)bPO3HT, xe2x80x94(CH2)aOCO(CH2)bPO3T2, xe2x80x94(CH2)aCONH(CH2)bPO3HT, xe2x80x94(CH2)aCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCO(CH2)bPO3HT, xe2x80x94(CH2)aNHCO(CH2)bPO3T2, xe2x80x94(CH2)aNHCONH(CH2)bPO3HT, xe2x80x94(CH2)aNHCONH(CH2)bPO3T2, xe2x80x94(CH2)aNHCSNH(CH2)bPO3HT, xe2x80x94(CH2)aNHCSNH(CH2)bPO3T2, xe2x80x94(CH2)aOCONH(CH2)bPO3HT, and xe2x80x94(CH2)aOCONH(CH2)bPO3T2, xe2x80x94CH2(CH2xe2x80x94Oxe2x80x94CH2)cxe2x80x94CH2xe2x80x94OH, xe2x80x94(CH2)dxe2x80x94CO2T, xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)exe2x80x94CH2xe2x80x94CO2T, xe2x80x94(CH2)fxe2x80x94NH2, xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)gxe2x80x94CH2xe2x80x94NH2, xe2x80x94(CH2)hxe2x80x94N(Ra)xe2x80x94(CH2)ixe2x80x94CO2T, and xe2x80x94(CH2)jxe2x80x94N(Rb)xe2x80x94CH2xe2x80x94(CH2xe2x80x94Oxe2x80x94CH2)kxe2x80x94CH2xe2x80x94CO2T; W6 and X6 are selected from the group consisting of xe2x80x94CRcRd, xe2x80x94Oxe2x80x94, xe2x80x94NRc, xe2x80x94Sxe2x80x94, and xe2x80x94Se; V6 is a single bond or is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sexe2x80x94, and xe2x80x94NRa; D6 is a single or a double bond; A6, B6 and E6 may be the same or different and are selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sexe2x80x94, xe2x80x94Pxe2x80x94, xe2x80x94NRa, xe2x80x94CRcRd, CRc, alkyl, and xe2x80x94Cxe2x95x90O; A6, B6, D6, and E6 may together form a 6 or 7 membered carbocyclic ring or a 6 or 7 membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom; a, b, d, f, h, i, and j independently vary from 1-10; c, e, g, and k independently vary from 1-100; a6 and b6 vary from 0 to 5; Ra, Rb, Rc, and Rd are defined in the same manner as Y6; T is either H or a negative charge.
The inventive compositions and methods are advantageous since they provide a real-time, accurate, repeatable measure of renal excretion rate using exogenous markers under specific yet changing circumstances. This represents a substantial improvement over any currently available or widely practiced method, since currently, no reliable, continuous, repeatable bedside method for the assessment of specific renal function by optical methods exists. Moreover, since the inventive method depends solely on the renal elimination of the exogenous chemical entity, the measurement is absolute and requires no subjective interpretation based on age, muscle mass, blood pressure, etc. In fact it represents the nature of renal function in this particular patient, under these particular circumstances, at this precise moment in time.
The inventive compounds and methods provide simple, efficient, and effective monitoring of organ function. The compound is administered and a sensor, either external or internal, is used to detect absorption and/or emission to determine the rate at which the compound is cleared from the blood. By altering the R groups, the compounds may be rendered more organ specific.